1. Field of the Invention
The present invention is directed to polymineralic particles which are precursors of hydroxyapatite and a method for their production. The present invention is also directed to a synthetic bone-like or dental composition comprising said hydroxyapatite polymineralic precursor particles of hydroxyapatite and optionally, a polymeric material capable of promoting mineralization of hydroxyapatite, which are useful for fixing prosthetic devices, useful as bone substitutes to directly fill bone defects, to provide substrates for cartilage, and to repair teeth, and methods of making such preparations. The present invention is also directed to a method of treating collagen to provide a micro-structure close to that of native bone.
2. Description of Related Art
The microstructural features of teeth and bone and the processes by which remodeling occurs are of importance in determining desirable microstructures in bone-like substitutes. Because bone substitutes must emulate the function of bone, bone must bond well with them. The nature of this bonding will depend on the pore sizes in the polymeric material capable of forming mineralization of hydroxyapatite. It has been shown that the response of bone to porous implants depends on the pore size. Bone growth occurs in close apposition to an implant which contain 40 .mu.m pores regardless of whether the implant is a metallic or a ceramic material. For pore sizes of 100 .mu.m, bone will fill in the pore and for pores sizes in excess of approximately 150 .mu.m Haversion systems will develop and facilitate the formation of a strong bond with the bone substitute. The ability to directly control microstructural development in a prosthesis composed of a resorbable material and consequently to control its porosity has a major influence on bone intergrowth and prosthesis remodeling. Unfortunately, mechanical integrity and porosity are conflicting functional requirements. Thus, it is unlikely that a single material would be capable of meeting the function requirements of bone. Indeed, none has been found. The alternative is to develop a composite which would exhibit adequate mechanical properties along with the porosity needed to meet the biological requirements for remodeling.
There have been many attempts to prepare a substitute bone material and there are numerous patents disclosing methods of preparation of such substitute bone materials. U.S. Pat. No. 4,440,750 to Glowacki, et al. discloses a plastic dispersion of demineralized bone powder and reconstituted native atelopeptide collagen fibers in a continuous aqueous phase to repair or construct bone by injecting or implanting it at the repair or constructive site. U.S. Pat. No. 4,516,276 to Mittelmeier employs collagen as a fleece described as a grid or network which is than dusted with apatite powder or granules, or the fiber material is mixed with mineral before being formed into layers for implantation into bone. Some patents claim the use of porous hydroxyapatite, for example U.S. Pat. No. 4,629,464 discloses a method for preparation of artificial bone material where sintered microporous hydroxyapatite is used either in a granular or slurried form in a physiological saline solution or in a form of a shaped prosthetic bone substitute. The prepared bone substitute is characterized by an open porous structure. Such an open porous structure allows for ingrowth of natural tissue. Another method and composition of material promoting the growth of bone is disclosed in U.S. Pat. No. 5,073,114. The bone growing composition includes two sizes of hydroxyapatite for supporting the growth of the bone, tetracycline for its antibiotic effect, freeze-dried decalcified human bone for promoting bone growth and fibronectin for promoting connective tissue generation and for gelling the bone growing composition. U.S. Pat. No. 4,776,890 introduces a process for obtaining a matrix of mineral particles in reconstituted atelopeptide collagen comprising reconstituting a mixture of mineral particles with collagen in solution. However, none of the above discussed bone substitutes undergo reaction in vivo which would lead to their exhibiting mechanical properties comparable to those of natural bone.
U.S. Pat. Nos. 4,880,610; 5,047,031; and 5,053,212 to Constantz disclose calcium phosphate compositions useful as cements. The process involves merely mixing two dry ingredients, i.e., a calcium source and a phosphoric acid source to form a kneadable mixture. None of these references disclose or suggest the preparation of polymineralic precursor particles capable of forming hydroxyapatite without additional sources of calcium or phosphate, by reacting a calcium source and a phosphoric acid source in a non-aqueous liquid and then removing the non-aqueous liquid, which can be stored in a dry state and which are stable over long periods of time.
In U.S. Pat. No. 5,053,212, water is liberated in the mechanical mixing of the calcium source with the acidic phosphate source. Disadvantageously, this liberation of water is free to combine with the calcium and acidic phosphate sources which results in calcium phosphates which are slow to react to form HAp, and upon reaction to form HAp again release water, thereby increasing the porosity and limiting the mechanical strength of the resultant product.
W. Brown and Chow, U.S. Pat. No. 4,612,053, disclose mechanically mixing Ca.sub.4 (PO.sub.4).sub.2 O with at least one other calcium phosphate selected from the group consisting of CaHPO.sub.4.2H.sub.2 O, CaHPO.sub.4, Ca.sub.8 H.sub.2 (PO.sub.4).sub.4.5H.sub.2 O, (i.e., Ca.sub.8 (HPO.sub.4).sub.2 (PO.sub.4).sub.4.5H.sub.2 O), .alpha.-Ca.sub.3 (PO.sub.4).sub.2, .beta.-Ca.sub.3 (PO.sub.4).sub.2 and modified Ca.sub.3 (PO.sub.4).sub.2 for use in a dental restorative powder, paste and/or slurry. This mechanical mixing does not result in a reaction between Ca.sub.4 (PO.sub.4).sub.2 O and the recited calcium phosphates to form polymineralic precursor particles and thus does not disclose or suggest the use of the preparation of polymineralic precursor particles capable of forming hydroxyapatite without additional sources of calcium and phosphate, and which said particles can be stored in a dry state for long periods of time and which when mixed with a polymeric material capable of promoting mineralization of hydroxyapatite, can completely react to form phase-pure hydroxyapatite in vivo within a surgically relevant time of less than 4 hours, particularly less than 2 hours, as in the present invention.
The above discussed patents to W. Brown and Chow and Constanz rely on grinding mixtures of particles to a high fineness, which particles in admixture are then reacted in an aqueous solution to form hydroxyapatite.
Neither U.S. Pat. No. 4,612,053, nor U.S. Pat. Nos. 4,880,610, 5,047,031 or 5,053,212 disclose the preparation of polymineralic precursor particles capable of forming hydroxyapatite which are formed as a result of a chemical reaction between a calcium source and an acidic phosphate source having at least two protons bound to one phosphate in a non-aqueous liquid and wherein said polymineralic precursor particles are comprised of Ca.sub.x (PO.sub.4).sub.y and unreacted calcium phosphate, and utilizing the same in preparing hydroxyapatite compositions useful as a bone-like substitute or dental composition of the present invention.
The difference between the products of the above discussed patents and the polymineralic precursor particles of hydroxyapatite of the present invention is that each polymineralic particle of the present invention is capable of producing phase pure hydroxyapatite independently and regardless of the presence of any additional additives present in the composition. On the contrary, the compositions of the above described patents utilize physical mixtures of calcium source and acidic phosphate source, i.e., are blends of particles, and additional additives will have an effect on the purity of the HAp produced or on the ability to produce HAp at all.
The present invention is directed to a method of preparation of polymineralic precursor particles capable of forming hydroxyapatite which can be stored over a long period of time, and a composition of hydroxyapatite and polymeric material which is capable of promoting mineralization of hydroxyapatite which, besides exhibiting biocompatibility and the mechanical characteristics required for teeth or artificial bone, can be formed in a surgically relevant time, e.g., usually under 4 hours, particularly under 2 hours. The polymineralic precursor particles of the present invention are formed by chemically reacting a calcium source with the acidic phosphate source to form stable precursor particles which can be stored for long periods of time. No other inventions or publications identified report polymineralic precursor particles capable of forming hydroxyapatite, or a hydroxyapatite composition that can develop bone-like properties in vivo within a surgically relevant time at physiological temperature (body temperature). Further, most of the prior art requires prosthesis preparation in advance of surgery. This complicates treatment and requires taking measurements and separately fitting of the implant. The present invention introduces an novel way of preparing hydroxyapatite at physiological temperature to provide the surgically relevant time of reaction; hydroxyapatite formation is complete within hours, usually within four hours.
The advantages of using the hydroxyapatite composition of the present invention as a bone substitute are that the properties can be tailored to serve a variety of needs. These include development of the microstructures of both cancellous (porous) and cortical (dense) bone. In addition, the proportions of the constituent ingredients can be adjusted accordingly as a means of controlling the rate and extent of remodeling. Remodeling is the term used to describe the process of bone replacement. Remodeling in synthetic bone may be particularly desirable when younger individuals are involved. Remodeling can be achieved when defects are filled with osteoinductive (bone-forming) materials.
The formation of a hydroxyapatite composition of the present invention in vivo is important in a variety of circumstances like gap filling and bone fragment stabilization. A synthetic material to fill bone defects that is compatible with decalcified bone has not been before identified and there has been a long felt need in the art. The initiation of any bone remodeling procedure will occur more rapidly if a hydroxyapatite-based prosthesis can be placed into close or microscopic apposition with bone. As a result of the present invention, the present method is amenable to placement of a bone-like composition of the reactants into close apposition with bone. This would eliminate the existence of a macroscopic gap between a synthetic hydroxyapatite-based prosthesis and bone or to fill gaps between a metallic prosthesis and bone. The development of union would be promoted in both instances, as a result of the present invention.